Removal Of Microbubbles Through Drip Chamber Nucleation Sites

ABSTRACT

A drip chamber is provided that includes a hollow body and a nucleation column extending into the interior of the hollow body or formed on the inner surface of a drip chamber sidewall. The nucleation column can be formed with, or treated by a treatment to include, microfeatures or other surface properties that provide nucleation sites for the nucleation and amalgamation of microbubbles. The drip chamber can include a bubble catcher in the bottom of the hollow body and the nucleation column can extend from the bubble catcher into the interior of the hollow body. Methods of making such drip chambers are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/168,852, filed Oct. 24, 2018, which in-turn claims the benefit under35 U.S.C. § 119(e) of prior U.S. Provisional Patent Application No.62/585,838, filed Nov. 14, 2017, both of which are incorporated hereinin their entireties by reference.

BACKGROUND

During the course of hemodialysis, defects in the extracorporeal bloodcircuit can allow air to enter the bloodstream. For this purpose, ahemodialysis machine contains an air detector, a level detector, and abubble catcher in a venous drip chamber.

Miniscule amounts of air, for example, less than 200 μm, can be releasedinto the bloodstream as microbubbles. Most bubble catchers in venousdrip chambers are totally ineffective at capturing bubbles less than 50μm. Microbubbles of such small size cannot be filtered out or trapped bya bubble catcher because using a screen small enough for such filteringwould impede blood flow. New research shows that microbubbles are acause for concern. Microbubbles have been linked to lung injuries anddamage to the brain in hemodialysis patients, as described in theNational Institutes of Health publicationhttps://www.ncbi.nlm.nih.gov/pubmed/23826686.

Bubble catchers are known for separating air bubbles from blood, forexample, from U.S. Pat. No. 3,961,918 to Johnson, U.S. Pat. No.4,334,988 to Milligan, U.S. Pat. No. 5,980,741 to Schnell et al., U.S.Pat. No. 6,010,623 to Schnell et al., U.S. Pat. No. 8,430,834 B2 toKopperschmidt; U.S. Pat. No. 8,852,135 to Beden et al., and U.S. Pat.No. 9,316,523 B2 to Schneider et al., each of which is incorporatedherein in its entirety by reference.

Despite many different designs, a need still exists for a drip chamberthat provides a means for microbubbles to collect and amalgamate intolarger bubbles that can rise to a blood/air interface in the dripchamber or be easily trapped and prevented from entering a venous bloodreturn line.

SUMMARY

The present invention provides a drip chamber that more effectivelyseparates and captures microbubbles compared with conventional dripchambers. The drip chamber provides sites for microbubbles to collectand amalgamate into larger bubbles that can rise to the blood/airinterface in the chamber or be easily trapped and prevented fromentering a venous blood return line. According to various embodiments,the drip chamber comprises a hollow body having a top and a bottom, aninlet in fluid communication with the hollow body, an outlet in fluidcommunication with the hollow body at the bottom of the hollow body, anda nucleation column extending into the interior of the hollow body. Thenucleation column has an outer surface and can have any of a variety ofcross-sectional shapes, for example, square, polygonal, circular,ring-shaped, triangular, star-shaped, and the like. The hollow body canbe defined by a sidewall that defines the interior. The nucleationcolumn can be formed with, or treated by a treatment to include,microfeatures or other surface properties that provide nucleation sitesfor the nucleation and amalgamation of microbubbles in a liquid thatcontacts the outer surface, for example, blood.

The nucleation column provides abundant and/or efficient nucleationsites for promoting microbubble attachment and amalgamation. The dripchamber can be free of a nucleation column and the inner surface caninstead be provided with abundant and/or efficient nucleation sites.Information about nucleation sites and how they work can be found athttps://www.quora.com/What-are-nucleation-sites-and-how-do-they-work,which is incorporated herein in its entirety by reference.

The drip chamber can further comprise a bubble catcher in the bottom ofthe hollow body. The bubble catcher can provide flow passages thatprovide fluid communication between the interior of the hollow body andthe outlet. The nucleation column can extend from the bubble catcherinto the interior of the hollow body.

The drip chamber can be used in a hemodialysis machine such as shown inFIG. 1. The hemodialysis machine can include a drip chamber 10, a leveldetector 12 for detecting the level of blood in drip chamber 10, abubble catcher 14, a venous clamp 16, and an optical bubble detector 18.According to the present invention, the drip chamber can be formed with,or treated to provide, nucleation sites for the attachment andamalgamation of microbubbles.

Nucleation sites are microscopic features or imperfections on or insurfaces that allow bubbles to hold on. FIG. 2 shows an example ofnucleation occurring at a fingertip submerged in liquid where theirregular surface of the finger enables bubbles to stick. Creating anirregular inner surface in a venous drip chamber, for example, as shownin FIG. 3, by providing additional surface area, surface features,and/or surface properties, can be used to capture, that is, make stick,more and smaller microbubbles.

FIG. 4 further demonstrates this principle on a silicon surface thatappears smooth but catches air microbubbles in a flow of water flowingacross the surface. The surface also enables captured microbubbles toamalgamate into larger bubbles that can then be strained out by a bubblecatcher.

According to various embodiments, a nucleation column is created in thevenous drip chamber by providing the bubble catcher with a nucleationcolumn attached. The bubble catcher can itself be provided with amicroscopically rough surface, as shown in FIG. 5. FIG. 5 is describedin greater detail below. In the example shown in FIG. 5, the blood, onits way back to the patient, flows into the venous drip chamber where acombination of turbulence and irregular surfaces collect and growmicrobubbles into bubbles of a size that can rise to the blood/airinterface or readily be filtered out.

While improving bubble detectors can be important, attacking the problemof microbubbles themselves and preventing them from ever reaching thefinal safeguard of a bubble detector is an even more effective way ofobviating the problem.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a photograph showing a venous module for capturing air in ablood circuit.

FIG. 2 is a photograph showing nucleation occurring on a fingertipsubmerged in a liquid.

FIG. 3 is a microphotograph showing features on an irregular surface,under an electron microscope.

FIG. 4A is a photograph showing a plastic utensil surface catching airbubbles from a flow of water.

FIG. 4B is an enlarged photograph of the plastic utensil shown in FIG.4A and showing how bubbles on the surface amalgamate into largerbubbles.

FIG. 5 is a front view of a drip chamber comprising a bubble catcher inthe bottom of the drip chamber, a nucleation column, a blood tube goinginto the drip chamber, a pressure transducer tube in fluid communicationwith and leading away from the headspace in the drip chamber, and amedication port tube leading into the drip chamber.

DETAILED DESCRIPTION

According to various embodiments, a drip chamber having a nucleationcolumn is provided having abundant and efficient nucleation sites topromote microbubble attachment and amalgamation. The nucleation columncan be formed of a material comprising plastic, glass, or the like. Thenucleation column can be formed to extend into the interior of the dripchamber. It can be mounted at or near the top, the bottom, a side, or asidewall of the drip chamber. The inner surface of the drip chamber, thenucleation column, or both, can be treated or formed to provide thenucleation sites. When treated, the material can exhibit more and/ormore effective nucleation sites compared with the same material underthe same conditions but that has not been treated. The surface of thenucleation column, inner surface, or both, can be molded to include, ortreated to provide, surface features providing nucleation sites.

The surface features formed on the surface can be textured, patterned,sintered, sanded, sand-blasted, etched, porous, rough, pitted, foamed,grooved, cross-hatched, striated, or otherwise formed to promotenucleation and amalgamation of trappable gas bubbles from microbubblesin the drip chamber. The material of each of the nucleation column andthe drip chamber sidewall can independently be transparent, translucent,opaque, or non-transparent and the drip chamber itself can betransparent, translucent, opaque, or non-transparent. In addition to, oras an alternative to, texturing, the nucleation column and/or dripchamber sidewall can be coated on a surface thereof, with a coatingmaterial that forms a coating exhibiting abundant and efficientnucleation sites, that is, having improved nucleation efficiencyrelative to the same surface but without the coating. The sites promotethe nucleation of microbubbles and amalgamation thereof to form gasbubbles that are large enough to rise to the blood/air interface or betrapped by a drip chamber bubble catcher or bubble trap. Particularmaterials that can be coated include those having a surface comprisingplastic, sintered material, textured material, glass, ceramic, metal, ora primed or pre-coated surface. A smooth surface can be coated with acoating that provides nucleation sites in the form of surface features.A coating that provides abundant and efficient nucleation sites can beprovided on surfaces that are porous, smooth, rough, pitted, foamed,grooved, cross-hatched, striated, or that otherwise have, or lack,patterned or non-patterned physical features.

The nucleation efficiency of the inner surface coating depends on anumber of factors including the material of the drip chamber that iscoated and the type, amount, and population of chemical groups presenton the exposed surface of the coating. An improvement of 5% or more, inthe number of nucleation sites, represents an improved nucleationefficiency, although improvements in surface populations of nucleationsites of 10% or more, 20% or more, 30% or more, or 50% or more can beprovided and/or considered an improvement in nucleation efficiency, thatis, to be considered to have improved nucleation efficiency. Regardlessof any increase in population, or factored together with an increase inpopulation, nucleation efficiency can be measured as increasedmicrobubble production and release. The increased production can bemeasured optically, for example, by measuring production from acalibrant, microbubble-containing mixture, such as blood. Improvementsin the form of increased microbubble production of 5%, 10%, 20%, 30%,50%, or more can be considered to represent an improvement in nucleationefficiency.

Methods of forming surface features that can be useful as nucleationsites can depend on the material used for the drip chamber. Tooling ormachining can be used to form surface features on the nucleation columnor inner surface of the drip chamber. The nucleation sites can beprovided on both the nucleation column and the drip chamber innersurface. Exemplary methods include embossing, scratching, machining,micromachining, sanding, sand-blasting, channeling, pitting, ablating,melting, sintering, heat-treating, laser-treating, chiseling, drilling,and like methods, and combinations thereof.

Chemical treatment methods can be used to form surface features on thenucleation column or inner surface of the drip chamber. Chemicalsolvents or chemical etchants can be used to etch, partially dissolve,or otherwise deform, degrade, or roughen the surface to form physicalmicrofeatures thereon or therein. Any suitable etchant that can bematched to the nucleation column material or drip chamber material canbe used to control the amount and/or rate of surface treatment. As anexample, an aggressive etchant can be used on more robust materials.Tetra-Etch® fluorocarbon etchant, available from Polytetra ofMönchengladbach, Germany, can be used, for example, to etch fluorocarbonmaterials such as those comprising polytetrafluoroethylene and otherfluorocarbons. Acid etchants can be used to etch silica materials andother materials, including, for example, polysulfone, polyvinylchloride,polyvinylidene, and polycarbonate. Nucleation columns and drip chambersmade of Biofine® (available from Fresenius Medical Care Deutschland GmbHof Bad Homburg, Germany) and other polyolofine materials can be used andcan be etched with acid etchants and the like. Biofine® is a preferredmaterial for a nucleation column because of its biocompatibility and itsability to be stream sterilized at a temperature of 121° C. Both thenucleation column and the inner surface can comprise the same materialand can be etched with the same or different etchants.

Nucleation columns and drip chamber inner surface can be molded, forexample, by processes that themselves result in the formation of surfacefeatures providing nucleation sites. Extrusion molding, spinning,melt-spinning, co-extrusion, and other molding methods can be used.

According to various embodiments, the bubble catcher in the drip chambercan be made of the same material as the nucleation column, drip chamber,both, or any other material as described herein. Like the nucleationcolumn, the bubble catcher can also comprise nucleation site-formingsurface features formed thereon as described herein.

Drip chambers according to the present invention can have at least onenucleation site surface. The drip chamber can have at least one interiorwall that defines a reservoir portion for containing a volume of liquid,specifically, blood, and at least one opening in communication with thereservoir portion. According to various embodiments, the drip chamber iscoated on its inner surface, or interior wall, and on the areasurrounding and forming the opening, with a polymer coating thatprovides nucleation sites.

Exemplary materials that can be used to manufacture the drip chambers ofthe present invention, for example, those including a nucleation column,include polypropylene, polyethylene, polyethyleneterephthalate,polystyrene, polycarbonate, and cellulosics. More expensive plasticssuch as polytetrafluoroethylene and other fluorinated polymers can beused. Some drip chambers made from these plastics are hydrophobicwithout any additional coating. Herein, the term “hydrophobic” refers toa surface exhibiting an average surface energy of about 40 dynes/cm orless. While hydrophobic inner surfaces are desired as blood will notcling to the surface, extremely hydrophobic surfaces, i.e., havingsurface energies of 20 dynes/cm or less, may not be desired because gasbubbles tend not to cling to such surfaces and do not tend to amalgamateinto trappable microbubbles. Polypropylene is inexpensive and quitehydrophobic itself, and can be used as a material for the nucleationcolumn and/or drip chamber sidewall of the present invention.

In addition to the materials mentioned above, examples of other suitablematerials for the nucleation column and/or drip chamber sidewall includepolyolefins, polyamides, polyesters, silicones, polyurethanes, epoxies,acrylics, polyacrylates, polyesters, polysulfones, polymethacrylates,polycarbonate, PEEK, polyimide, polystyrene, and fluoropolymers such asPTFE Teflon®, FEP Teflon®, Tefzel®, poly(vinylidene fluoride), PVDF, andfluoroalkoxy resins. Glass products including silica glass can also beused to manufacture the nucleation columns and/or drip chamber sidewall.One exemplary glass product is PYREX® (available from Corning Glass,Corning, N.Y.). Coated surfaces of glass, silicon, silicon compounds,and ceramics that have or have not been primed with silane-containingmaterials or other adhesion promoting materials can also be used. Primedglass, primed ceramic, and primed oxide surfaces can be coated to formthe nucleation column and/or drip chamber sidewall according to variousembodiments. Surfaces that have been pre-coated with epoxies, silicones,urethanes, acrylics, or other materials can be coated to form thenucleation column and/or drip chamber sidewall according to variousembodiments of the invention.

The nucleation column exposed surface and/or drip chamber inner surfacecan have any suitable surface energy but surface energies of from about35 dynes/cm to about 60 dynes/cm can be preferred. Materials providinghigher or lower surface energies can also be used. An exemplary range ofpreferred surface energies can be the range of from about 39 dynes/cm toabout 46 dynes/cm.

According to various embodiments, the inner surface of the drip chamberis at least partially coated with a coating formulation. A delineatedarea of the inner surface can be free of, that is, not coated with, thecoating formulation, but can instead be surrounded by the coating. Thecoating thus forms a boundary to promote the nucleation of bubbles atonly certain areas of the drip chamber. The uncoated locations may havesurfaces that, for example, have specific affinities, optimize thesample volume to area ratio, or restrict gas bubbles movement. Theuncoated region may be surrounded by a hydrophobic coating material, forexample, comprising microparticles. According to various embodiments,the inner surface of the drip chamber can be partially coated with ahydrophobic coating formulation and partially coated withnon-fluorinated material in delineated regions.

According to various embodiments, the inner surface of the drip chambercan be provided with a first coating and a second coating. The secondcoating can comprise the reaction product, for example, thepolymerization product, of a second reactant, for example, a fluorinatedmonomer. The second reactant can have, for example, from about 3 toabout 20 carbon atoms, and can be combined with a surface rougheningagent, for example, a micropowder that provides the second coating witha rough surface and abundant nucleation sites.

In various embodiments, microscopic fibers such as cellulose or glassmicrofibers can be used with, or in place of, microparticles to providesurface roughness and nucleation sites. Preferably, cellulose and/orglass microfibers are used that have average diameters of from about oneto about 100 microns and lengths of from about 20 to several hundredmicrons. The microfibers can be admixed to increase the mechanicalstrength of the coating.

According to various embodiments, rough surfaces providing goodnucleation sites can be produced by employing foaming and/orpore-forming agents in the coating compositions. Foaming andpore-forming agents that may be used include spirocarbonates, diazocompounds, compressed gases, dissolved gases, volatile liquids, andcombinations thereof. The agents may be activated by heat, light, orvacuum during the drying, curing, and/or hardening of the coatingcomposition.

According to various embodiments, nucleation sites on the nucleationcolumn or on the inner surface of a drip chamber can be formed from acoating formulation comprising microparticles and the reaction productof a monomeric reactant. The microparticle-containing coating providesnucleation sites for the attachment of and amalgamation of microbubbles.

In various embodiments, a coating is provided by adhering to a surfaceroughening agent, for example, a micropowder, to the surface of areaction product, wherein the coating has an exposed surface areapopulated with 5% or more fluoromethyl groups. A coating can be formedwith a surface roughening agent having a surface area populated with 5%by area or more trifluoromethyl groups, wherein the surface rougheningagent is adhered to the hydrophobic surface. The adherence of thesurface roughening agent to the surface may be due to one or moremechanisms including, but not limited to, sintering the agent onto thesurface, curing a component of the surface and/or of a component of theagent, melting the surface and/or the agent, using like methods, or anycombination thereof. The surface roughening agent, for example, amicropowder, can be dusted onto the surface.

The present invention also provides processes of preparing surfaceroughening agent-containing surfaces. According to various embodiments,a coating formulation is applied to the nucleation column or to theinner surface of the drip chamber to form a coating having an exposedsurface area exhibiting a surface energy of from about 35 dynes/cm toabout 60 dynes/cm, for example, from about 39 dynes/ cm to about 46dynes/cm. Then, fluidized surface roughening agent microparticles areapplied and adhered to the coating to provide a rough surface. Theadherence of the agent to the coating may be due to one or moremechanisms including, but not limited to, sintering the agent onto thesurface, curing a component of the coating and/or a component of theagent, melting the coating and/or the agent, by like methods, or anycombination thereof.

The coating composition can be diluted with an appropriate solvent ormedium to obtain a coating solids content, or a non-volatile componentscontent, of from about 0.01% by weight to about 50% by weight, forexample, from about 0.1% by weight to about 2% by weight, depending uponthe application technique and desired coating properties.

Lower surface tensions can be obtained when the coating polymercomprises the polymerization product of a fluoroalkyl monomer or aperfluoroalkyl monomer, when compared to coatings comprising the productof a non-fluorinated or mostly non-fluorinated monomer. Substantiallynon-branched alkyl ethylenically unsaturated monomers can be used toproduce surfaces exhibiting surface tensions of from about 30 dynes/cmto 60 dynes/cm and that provide good nucleation sites. Materials andcoatings that provides surface energies of from about 35 dynes/cm toabout 55 dynes/cm, or from about 39 dynes/cm to about 46 dynes/cm, canbe preferred according to various embodiments. A methacrylate group canbe used as an ethylenically unsaturated monomer for making a coating onthe nucleation column or on the drip chamber sidewall. Other monomersthat can be used include silicones, epoxies, and urethanes. Otherreactants that can be used include anhydrides, amines, polyols, vinyls,vinyl ethers, and mixtures thereof. Polymers made from mixtures ofacrylates and epoxies, or of acrylates and silicones, can be used.According to various embodiments, the nucleation column or the dripchamber inner surface can be provided with a coating thereon, andoptionally a durable resinous component such as a urethane orpolyurethane component. Coating solutions can be used at full strengthbut may be diluted, for example, with a fluorosolvent, to form lowconcentrations of coating polymer. The polymer solution used to make thecoatings can have a coating polymer content of from about 0.01% byweight to about 50% by weight.

Additives can be incorporated into or polymerized with the coatingpolymers and monomers used to provide coatings having improvedtoughness, chemical resistance, hardness, softness, processability,elasticity, adhesion, color, texture, thickness, and/or ultraviolent(UV)-resistance. Hydrophilic additives can be used and can provideattachment surfaces in the form of nucleation sites to attract, attach,and amalgamate microbubbles. Channels having gradients of hydrophobicityto hydrophilicity can be provided to channel, move, and directmicrobubbles together or toward a common microbubble amalgamationlocation where they can merge together to become a single, larger,trappable microbubble. Grooves having different coating materials, agradient of coating, thicknesses, or both, can be used, for example, toform such channeling features. Chemically resistant additives can beused. Additives including reactants and/or monomers can be added inamounts ranging from 1% by weight to about 95% by weight and aredescribed in more detail below.

Coating compositions can be used that combine nucleation site-formingparticles and chemically resistant non-fluorinated resins such asacrylics, cellulosics, epoxy, polyesters, silicones, urethanes,anhydrides, amines, polyols, vinyls, vinyl ethers, and combinationsthereof. These mixtures can produce surfaces exhibiting any of a rangeof surface energies and abundant nucleation sites.

According to various embodiments, the coating composition can comprisean aromatic or aliphatic polyurethane. The coating can comprise thepolymerization product of an isocyanate-containing monomer. The coatingcan further comprise a cellulosic, a polyester, the polymerizationproduct of an unsaturated monomer, a condensation polymer, a siliconepolymer, an epoxy, or a combination thereof.

According to various embodiments, hydrophobic coatings are made of apolymerization product of a fluorinated monomer and a small amount of aco-monomer, for example, a silane, that serves to promote adhesion ofthe coating to the nucleation column or drip chamber inner surfacewithout compromising the surface energy of the coating. Coupling agentscan also be used as adhesion promoting monomers. Such silanes andcoupling agents, if present, can be present in amounts of from 1% byweight to about 10% by weight, or from about 2% by weight to about 5% byweight.

Aqueous suspension formulations that can be used can include additivesas discussed above, including epoxy resins. Exemplary waterborne epoxyresins that can be used in aqueous suspension coating formulationsinclude the EPI-REZ Resins from Shell Chemical Company, for example, theEPI-REZ Resins WD-510, WD-511, WD-512, 3510-W-60, 3515-W-60, 3519-W-50,3520-WY-55 and 3522-W-60. The coating composition can comprisemicroparticles, microfibers, foaming and/or pore-forming agents, and canbe dried, cured, and/or hardened so as to produce sufficient surfaceroughness to provide abundant nucleation sites.

Another method of forming a coating for use on the nucleation column ordrip chamber inner surface is by using monomers capable of free radicallinkages. Such monomers can be attached to the nucleation column orinner surface of the drip chamber if the surface is first treated byionizing radiation or other means to generate free radicals across thesurface. A monomer capable of free radical linkages can be formed bymixing an alkyl ethylenically unsaturated monomer dissolved in asuitable solvent, with an effective amount of a free radical initiator.A nucleation column, for example, made of glass, can be coated with themixture are then heated to the temperature at which the free radicalinitiator initiates free radical generation. Many conventional azocompounds have an appropriate activation temperature, particularlywithin the range of from 30° C. to 200° C. Many azo compounds can beused which are activated by visible or UV light.

A microscopically roughened or porous surface can be made by addingmicroscopic particles of a surface roughening agent, for example,micropowder, to the coating material or to the surface to which thecoating formulation is to be applied.

Many microparticles can be used as surface roughening agents to formnucleation sites, including micropowders. Micropowders are definedherein as those powders or particles having average diameters of fromsubmicron sizes up to 100 microns. An exemplary micropowder averagediameter is about 10 microns or less. Suitable micropowders includesilicon glass particles with and without silane coatings, pigments,Teflon® powders, siliconized glass, fluorosiliconized inorganicpigments, and micronized cellulosics. According to various embodiments,a composite surface can be formed by adding a substantially uniformlysized micropowder to a polymer or a monomer that is to be subsequentlyapplied as a coating and then polymerized. The use of micropowdersexhibiting wide particle size distributions can also be used to providea coating providing an abundance of different nucleation sites.

Inert micropowders can be used. One exemplary micropowder is asiliconized glass particulate material having a 0.3 micron averageparticle size diameter available as TULLANOX HM 250 or TULLANOX HM 250D,from Tulco, Inc., of Ayer, Mass. Another exemplary micropowder isTeflon® MP 1200, available from DuPont Polymer Products Department,Wilmington, Del., and having an average particle diameter of about 4 μm.

Microfibers are another class of surface roughening agents that can beused in the coating compositions. An exemplary microfiber is a cellulosemicrofiber having an average diameter of about 4 microns and an averagelength of about 40 microns. Microfibers of longer lengths can also beused.

The methods of the present invention can comprise diluting a coatingpolymer solution or suspension prior to applying the solution orsuspension to the nucleation column or to the inner surface of a dripchamber. The coating solution or suspension can be diluted to be betweenabout 0.01% and 2% by weight coating polymer. Higher weight percentagesof the polymer can be used.

Another method of applying a coating polymer solution or suspensioncomprises dip-coating the nucleation column or drip chamber into apolymer solution or suspension. Other coating methods can also be used,including spray coating, tumbling in solution, brush coating, padding,rinsing, spraying, fogging, transferring, painting, printing,stenciling, screen printing, pad printing, ink jet printing, injectionmolding, laminating, and doctoring. For simultaneously coating a largenumber of nucleation columns or drip chambers a tumbling method ofcoating, for example, can be used.

Dip coating can be used according to various embodiments, to apply thecoating polymer from a solution of the polymer dissolved in a solvent orfrom a suspension of the polymer. After coating the polymer solution orsuspension, the coating is allowed to dry and solvent or carrier isdriven off.

According to various embodiments, the coating formulation is not apolymer solution or suspension but instead comprises a fluidizedmicropowder of the polymerization product of a monomer. The micropowderformulation can be applied to the inner surface of the drip chamber andmelted to form a coating having practically any desired surface energy.According to various embodiments, the coating formulation comprises afluidized micropowder of the polymerization product of a monomer, and atleast one substantially non-perfluorinated resin. The micropowder andresin are applied to the surface of the nucleation column or dripchamber sidewall and then heated to melt the fluidized micropowder.

According to various embodiments, the coating polymer or coating monomerformulation of the invention is applied as a micropowder along with atleast one of a curable resin and a non-curable resin. Preferably, the atleast one resin is substantially non-perfluorinated, for example,non-fluorinated. Curable resins that can be used in formulations ofmicropowder coating material include epoxy resins, urethane resins,acrylate resins, and methacrylate resins. An exemplary resin having ahigh crosslink density is the epoxy novolac resin D.E.N. 439, availablefrom Dow Chemical Co., Midland, Mich.

According to various embodiments, resins with low cross-link densitiescan be employed. An exemplary low crosslink density resin is the fusionsolid EPON Resin 1004F available from Shell Chemical Company, Houston,Tex. EPON Resin 1004F is a bisphenol A epoxy resin having a meltingpoint of about 100° C. Other EPON Resins from Shell Chemical Company canalso be used, including 1001F, 1002F, 1007F, and 1009F, as well as the2000 series powdered EPON Resins, for example, EPON Resins 2002, 2003,2004, and 2005.

Non-curable resins that can be employed include powdered ethylcellulose, powdered polyethylene, powdered polypropylene, and powderedpolyvinylidenedifluoride. Cellulose acetate butyrate pellets can be jetmilled and applied as a powder. Cellulose acetate butyrate is typicallynon-curable but can be cross-linked with peroxides.

The micropowders and resins can be formed, for example, by jet milling.The micropowders and resins are preferably particles having an averagediameter of about 50 microns or less, for example, having averagediameters of 10 microns or less. The powders can be electrostaticallysprayed onto the inner surface of a drip chamber with or without acuring agent. Micropowders can also be prepared as latexes in aqueoussuspensions, subsequently separated from the liquid phase, and dried.

In various embodiments, a surface is coated with a coating formulationcomprising a fluidized micropowder of a polymerization product and anon-melting micropowder that does not melt at temperatures required forformation of the coating. The formulation is then heated or sintered tomelt the fluidized polymerization product micropowder without meltingthe non-melting micropowder. The non-melting micropowder can be selectedfrom the group consisting of Teflon® micropowders, Tefzel® micropowders,Kynar® micropowders, polyvinylidene difluoride micropowders, silicamicropowders, and polypropylene micropowders.

According to various embodiments that involve forming coatings bymelting micropowders, the coating formulations can be applied as asuspension to the inner surface of the drip chamber and subsequentlydried prior to melting.

Another method of forming a nucleation column having abundant andimproved nucleation sites involves pre-injecting or co-injecting acoating or exposed surface formulation prior to or during the laminarflow of molten materials injected into a mold or through an orifice toform the nucleation column. The pre-injected or co-injected coatingformulation can comprise a thermoplastic resin and/or a thermosettingresin. The injectable coating formulation can comprise mixtures ofreactive monomer, catalyst, and resin. The injectable coatingformulation can comprise mixtures of molten prepolymerized monomer andmicroparticles, to form coatings exhibiting abundant, efficientnucleation sites. The injectable coating formulations can comprisemixtures of molten prepolymerized monomers, other resins, andmicroparticles, which are pre-injected or co-injected into or during thelaminar flow of molten materials injected into a mold. The flow caninstead be injected through an orifice to form a coating on theresultant nucleation column. The resulting surface can exhibit abundantand efficient nucleation sites and a low retention of biologicalsamples.

According to various embodiments, the coating composition has a volumeof hardenable resin that is less than the volume of microparticles inthe composition. The microparticles can comprise inorganic substances,can be porous, and can comprise clusters of smaller particles. Themicroparticles can have an average particle size diameter of from about1 micron to about 100 microns. In place of or in addition to themicroparticles, the composition can comprise nanoparticles having anaverage particle size diameter of less than about 100 nanometers. Thecoating composition can include both microparticles and nanoparticles,for example, up to about 30% by weight nanoparticles based on the weightof the microparticles, up to about 10% by weight nanoparticles, or fromabout 5% by weight to about 10% by weight nanoparticles. Nanoparticlessmaller than 30 nanometers can be used. The microparticles can beclusters of nanoparticles.

The hardenable resin of the composition can be hardened by radiation, bymoisture, by oxidation, by the addition of a hardener or co-resin, byheat, by evaporation of a solvent, by a combination thereof, or thelike. The hardenable resin can have a functionality of at least two, forexample, a functionality of at least three. The hardenable resin can beat least one resin of an acrylate, an alkyd, a urethane, an isocyanate,an epoxy, a fluorocarbon, a silicone, a siloxane, a silicate, a ceramic,a metal, a polyester, a vinyl, an anhydride, a polyimide, a polyol, or acombination thereof. The hardenable resin can comprise polyhexamethylenediisocyanate, methylene bis hexane isocyanate, and/or an ethoxylatedacrylic. The coating composition can include a hardenable resin,microparticles having an average particle size diameter of from about 1micron to about 100 microns, and/or nanoparticles having an averageparticle size diameter of less than about 500 nanometers. Thenanoparticles can have an average particle size diameter of less thanabout 100 nanometers. The microparticles can be made ofpolytetrafluoroethylene, a polytetrafluoroethylene copolymer, or acombination thereof. Such compositions can also include a volatilesolvent, for example, an at least partially fluorinated volatilesolvent. According to various embodiments, a composition of matter isprovided that includes a volume of hardenable resin, and a volume ofnanoparticles having an average particle size diameter of less thanabout 500 nanometers, wherein the volume of the nanoparticles is equalto or greater than the volume of the hardenable resin. The volume of thenanoparticles can be more than twice the volume of the hardenable resin.The nanoparticles can have an average particle size diameter of lessthan about 20 nanometers.

Another coating composition that can be used includes extremely finehydrophobic micropowders having average particle size diameters of fromabout 1 to about 100 nanometers (nm), for example, in an amount of fromabout 1.0% by weight to about 30% by weight based on the total weight ofthe non-volatile components of the coating composition. Average particlesizes of from about 1 nm to about 50 nm are exemplary, as are averageparticle sizes of from about 1 nm to about 10 nm. For example, hardresin formulations including Dupont's ZONYL 5069, having nanoparticleswith average particle size diameters in the range of from about 10 nm toabout 100 nm, and added in an amount of about 10 percent by weight basedon the weight of Dupont's ZONYL MP1000 in the formulation, can be used.

A process of improving a coating on the nucleation column or on theinner surface of a drip chamber is also provided that includes applyingto the coating a film or layer onto and conforming to at least theinterstitial surfaces of the coating. The film or layer can include ahardenable resin and a volume excess of particles. The film or layer canhave a thickness of less than about 2 microns, or a thickness of lessthan about half of the average interstitial pore size diameter of theinterstitial pores of the coating. The film can have a thickness of lessthan about 50 nanometers. The particles can have an average particlesize diameter of less than about 100 microns. The film or layer caninclude nanoparticles having an average particle size diameter of about500 nanometers or less.

A process of improving a surface having rough, porous, striated,embossed, particle-covered, or micropatterned features, is provided thatincludes applying to the surface a film or layer onto and conforming tothe surface. The features have at least one width dimension of about 100microns or less and are spaced about 100 microns or less apart. Featuresthat have a height greater than about half their width dimension can beused. The features can be created using abrading, etching, machining,micromachining, photolithography, laser ablation, molding, embossing orany means that produces a micro-featured surface. The film or layer caninclude a hardenable resin and/or a volume excess of particles. The filmor layer can have a thickness of less than about 10 microns, or athickness of less than about half of the average distance between therough, striated, embossed, particle-covered, or micropatterned featuresof the surface. The film can have a thickness of less than about 50nanometers. The particles can have an average particle size diameter ofless than about 100 microns. The film or layer can include nanoparticleshaving an average particle size diameter of about 500 nanometers orless. The resin to micropowder volume ratio can be, for example, fromabout one to about four. Hard epoxies, polyurethanes, and acrylics withhigh cross-link densities can be used and are exceptionally durable.

With reference FIG. 5, a transparent bubble catcher 50 is shown thatincludes a body 52, a cap 54, a bubble catcher 56, an inlet 58, and anoutlet 60. Body 52 has an inner surface 62, the lower portion of whichdefines a blood-contacting surface 64. A blood tube 66 is in fluidcommunication with the interior of drip chamber 50 through inlet 58.Blood tube 66 can be sealed to cap 54 at inlet 58, for example, bysealant, adhesive, solvent bonding, a friction fit, an O-ringconnection, co-molding, or the like. A hermetic seal can be provided.Cap 54 can be sealed to drip chamber body 52, for example, by sealant,adhesive, solvent bonding, a friction fit, an O-ring connection,co-molding, or the like. A hermetic seal can be provided. In addition tonucleation sites that may be provided by surface 64 of inner surface 62,a nucleation column 68 is provided extending from bubble catcher 56 andmakes up a nucleation site-providing feature. Nucleation column 68 canbe formed to include, or treated to provide, nucleation sites on theouter surface thereof. Herein, when describing materials, coatings, andmethods for forming nucleation column 68, the same materials, coatings,and methods can be used for forming nucleation sites on blood-contactingsurface 64 or the entirety of inner surface 62.

Nucleation column 68 can be integrally formed with bubble catcher 56 orformed separately then connected to bubble catcher 56. Nucleation column68 can be screwed into a threaded receptacle in bubble catcher 56,solvent-bonded to bubble catcher 56, or otherwise adhered or connectedto bubble catcher 56 and can intersect with bubble catcher 56 at anintersection 84. Nucleation column 68 and bubble catcher 56 can be3D-printed together or separately, co-molded, or molded together as asingle, unitary, monolithic structure. Nucleation column 68 can have adistal tip 86 that can terminate above, at, or below the typical levelof blood in drip chamber 50 during normal operation.

Drip chamber 50 is also connected to a pressure line 70 sealed to cap 54and leading to a pressure transducer (not shown). A clamp 72 is providedon pressure line 70. Pressure line 70 is in fluid communication with theheadspace in drip chamber 50 and, in operation, in fluid communicationwith the pressure transducer, to sense gas pressure within theheadspace.

Drip chamber 50 is also connected to a medication line 74 sealed to cap54 and through which medication, saline, or other liquids or substancescan be introduced into drip chamber 50. A clamp 76 is provided toclose-off medication line 74 when not in use. Luer or other connectors80 and 82 can be provided on the ends of pressure line 72 and medicationline 74, respectively, to sealingly connect them to other componentssuch as a pressure transducer or an intravenous line.

The present invention includes the followingaspects/embodiments/features in any order and/or in any combination:

1. A drip chamber for separating air from blood in a blood line, thedrip chamber comprising:

a hollow body having a top and a bottom;

an inlet in fluid communication with the hollow body;

an outlet in fluid communication with the hollow body at the bottom ofthe hollow body; and

a nucleation column having an outer surface,

wherein the hollow body is defined by a sidewall and has an interior,the sidewall has an inner surface, the nucleation column extends intothe interior, the nucleation column has been formed with, or treated bya treatment to form, microfeatures in or on the outer surface thatprovide nucleation sites for nucleation and amalgamation of microbubblesin a liquid that contacts the outer surface.

2. The drip chamber of any preceding or followingembodiment/feature/aspect, wherein the nucleation column comprises amaterial, a population of the microfeatures at the outer surface isgreater than a population of the microfeatures at a surface of the samematerial but that has not been formed with, treated with said treatmentto provide, the microfeatures.

3. The drip chamber of any preceding or followingembodiment/feature/aspect, further comprising a bubble catcher in thebottom of the hollow body, the bubble catcher providing flow passagesproviding fluid communication between the interior of the hollow bodyand the outlet.

4. The drip chamber of any preceding or followingembodiment/feature/aspect, wherein the nucleation column extends fromthe bubble catcher into the interior of the hollow body.

5. The drip chamber of any preceding or followingembodiment/feature/aspect, wherein the treatment comprises a coatingtreatment and the outer surface of the nucleation column comprises acoating.

6. The drip chamber of any preceding or followingembodiment/feature/aspect, wherein the treatment comprises at least oneof machining the outer surface, chemically etching the outer surface, orapplying a coating to the outer surface.

7. The drip chamber of any preceding or followingembodiment/feature/aspect, wherein the treatment comprises applying acoating to the outer surface, and the coating comprises microparticles.

8. A drip chamber for separating air from blood in a blood line, thedrip chamber comprising:

a hollow body having a top and a bottom;

an inlet in fluid communication with the hollow body; and

an outlet in fluid communication with the hollow body at the bottom ofthe hollow body,

wherein the hollow body is defined by a sidewall, the sidewall comprisesa material and has an inner surface, the inner surface has been treatedby a treatment to form microfeatures in or on the inner surface, apopulation of the microfeatures at the inner surface is greater than apopulation of the microfeatures at a surface of the same material butthat has not been treated with said treatment, and the microfeaturesprovide nucleation sites for nucleation and amalgamation of microbubblesin a liquid that contacts the inner surface.

9. The drip chamber of any preceding or followingembodiment/feature/aspect, further comprising a bubble catcher in thebottom of the hollow body, the bubble catcher providing flow passagesproviding fluid communication between an interior of the hollow body andthe outlet.

10. The drip chamber of any preceding or followingembodiment/feature/aspect, further comprising a nucleation columnextending from the bubble catcher into the interior of the hollow body.

11. The drip chamber of any preceding or followingembodiment/feature/aspect, further comprising a nucleation column insidethe hollow body.

12. The drip chamber of any preceding or followingembodiment/feature/aspect, wherein the treatment comprises a coatingtreatment and the inner surface of the hollow body comprises a coating.

13. The drip chamber of any preceding or followingembodiment/feature/aspect, wherein the treatment comprises at least oneof machining the inner surface, chemically etching the inner surface, orapplying a coating to the inner surface.

14. The drip chamber of any preceding or followingembodiment/feature/aspect, wherein the treatment comprises applying acoating to the inner surface, and the coating comprises microparticles.

15. A method of making a drip chamber, the method comprising:

providing a drip chamber comprising a hollow body having a top, abottom, an interior, a sidewall, an inner surface, and a nucleationcolumn extending into the interior, the nucleation column having anouter surface;

treating the outer surface with a treatment, the treatment increasing apopulation of nucleation sites along the outer surface; and

capping the hollow body at the top thereof with a cap comprising a bloodtube, to form a fluid communication between the blood tube and theinterior.

16. The method of any preceding or following embodiment/feature/aspect,wherein the treatment comprises chemically etching the inner surface.

17. The method of any preceding or following embodiment/feature/aspect,wherein the treatment comprises applying a coating to the outer surface.

18. The method of any preceding or following embodiment/feature/aspect,wherein the treatment comprises machining the outer surface.

19. The method of any preceding or following embodiment/feature/aspect,further comprising:

providing a bubble catcher in the interior; and

connecting the nucleation column with the bubble catcher.

20. The method of any preceding or following embodiment/feature/aspect,wherein the connecting the nucleation column with the bubble catchercomprises integrally forming the nucleation column and the bubblecatcher as a unitary, one-piece structure.

21. A method of making a drip chamber, the method comprising:

providing a drip chamber comprising a hollow body having a top, abottom, an interior, a sidewall, and an inner surface;

treating the inner surface of the hollow body with a treatment, thetreatment increasing a population of nucleation sites along the innersurface; and

capping the hollow body at the top thereof with a cap comprising a bloodtube, to form a fluid communication between the blood tube and theinterior.

22. The method of any preceding or following embodiment/feature/aspect,wherein the treatment comprises chemically etching the inner surface.

23. The method of any preceding or following embodiment/feature/aspect,wherein the treatment comprises applying a coating to the inner surface.

24. The method of any preceding or following embodiment/feature/aspect,wherein the treatment comprises machining the inner surface.

25. The method of any preceding or following embodiment/feature/aspect,further comprising:

providing a nucleation column within the interior; and

treating the nucleation column with a treatment to increase a populationof nucleation sites on the nucleation column.

26. The method of any preceding or following embodiment/feature/aspect,further comprising:

providing a bubble catcher at the bottom of the hollow body, wherein thenucleation column extends from the bubble catcher into the interior ofthe hollow body.

The present invention can include any combination of these variousfeatures or embodiments above and/or below, as set forth in theforegoing sentences and/or paragraphs. Any combination of disclosedfeatures herein is considered part of the present invention and nolimitation is intended with respect to combinable features.

Applicant specifically incorporates the entire contents of all citedreferences in this disclosure. Further, when an amount, concentration,or other value or parameter is given as either a range, preferred range,or a list of upper preferable values and lower preferable values, thisis to be understood as specifically disclosing all ranges formed fromany pair of any upper range limit or preferred value and any lower rangelimit or preferred value, regardless of whether such specific ranges areseparately disclosed. Where a range of numerical values is recitedherein, unless otherwise stated, the range is intended to include theendpoints thereof, and all integers and fractions within the range. Itis not intended that the scope of the invention be limited to thespecific values recited when defining a range.

Other embodiments of the present invention will be apparent to thoseskilled in the art from consideration of the present specification andpractice of the present invention disclosed herein. It is intended thatthe present specification and examples be considered as exemplary onlywith a true scope and spirit of the invention being indicated by thefollowing claims and equivalents thereof.

What is claimed is:
 1. A drip chamber for separating air from blood in ablood line, the drip chamber comprising: a hollow body having a top anda bottom; an inlet in fluid communication with the hollow body; and anoutlet in fluid communication with the hollow body at the bottom of thehollow body, wherein the hollow body is defined by a sidewall, thesidewall comprises a material and has an inner surface, the innersurface has been treated by a treatment to form microfeatures in or onthe inner surface, a population of the microfeatures at the innersurface is greater than a population of the microfeatures at a surfaceof the same material but that has not been treated with said treatment,and the microfeatures provide nucleation sites for nucleation andamalgamation of microbubbles in a liquid that contacts the innersurface.
 2. The drip chamber of claim 1, further comprising a bubblecatcher in the bottom of the hollow body, the bubble catcher providingflow passages providing fluid communication between an interior of thehollow body and the outlet.
 3. The drip chamber of claim 2, furthercomprising a nucleation column extending from the bubble catcher intothe interior of the hollow body.
 4. The drip chamber of claim 1, furthercomprising a nucleation column inside the hollow body.
 5. The dripchamber of claim 1, wherein the treatment comprises a coating treatmentand the inner surface of the hollow body comprises a coating.
 6. Thedrip chamber of claim 1, wherein the treatment comprises at least one ofmachining the inner surface, chemically etching the inner surface, orapplying a coating to the inner surface.
 7. The drip chamber of claim 6,wherein the treatment comprises applying a coating to the inner surface,and the coating comprises microparticles.
 8. A method of making a dripchamber, the method comprising: providing a drip chamber comprising ahollow body having a top, a bottom, an interior, a sidewall, an innersurface, and a nucleation column extending into the interior, thenucleation column having an outer surface; treating the outer surfacewith a treatment, the treatment increasing a population of nucleationsites along the outer surface; and capping the hollow body at the topthereof with a cap comprising a blood tube, to form a fluidcommunication between the blood tube and the interior.
 9. The method ofclaim 8, wherein the treatment comprises chemically etching the innersurface.
 10. The method of claim 8, wherein the treatment comprisesapplying a coating to the outer surface.
 11. The method of claim 8,wherein the treatment comprises machining the outer surface.
 12. Themethod of claim 8, further comprising: providing a bubble catcher in theinterior; and connecting the nucleation column with the bubble catcher.13. The method of claim 12, wherein the connecting the nucleation columnwith the bubble catcher comprises integrally forming the nucleationcolumn and the bubble catcher as a unitary, one-piece structure.
 14. Amethod of making a drip chamber, the method comprising: providing a dripchamber comprising a hollow body having a top, a bottom, an interior, asidewall, and an inner surface; treating the inner surface of the hollowbody with a treatment, the treatment increasing a population ofnucleation sites along the inner surface; and capping the hollow body atthe top thereof with a cap comprising a blood tube, to form a fluidcommunication between the blood tube and the interior.
 15. The method ofclaim 14, wherein the treatment comprises chemically etching the innersurface.
 16. The method of claim 14, wherein the treatment comprisesapplying a coating to the inner surface.
 17. The method of claim 14,wherein the treatment comprises machining the inner surface.
 18. Themethod of claim 14, further comprising: providing a nucleation columnwithin the interior; and treating the nucleation column with a treatmentto increase a population of nucleation sites on the nucleation column.19. The method of claim 18, further comprising: providing a bubblecatcher at the bottom of the hollow body, wherein the nucleation columnextends from the bubble catcher into the interior of the hollow body.